Gentiopicroside Ameliorates Diabetic Renal Tubulointerstitial Fibrosis via Inhibiting the AT1R/CK2/NF-κB Pathway.
Gentiopicroside Ameliorates Diabetic Renal Tubulointerstitial Fibrosis via Inhibiting the AT1R/CK2/NF-κB Pathway.
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龙胆苦苷通过抑制 AT1R/CK2/NF-κB 通路改善糖尿病肾小管间质纤维化
DOI：
10.3389/fphar.2022.848915
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发表时间：
2022
影响因子：
5.6
通讯作者：
Huang, Heqing
中科院分区：
文献类型：
--
作者：
Xu, Zhanchi;Zhang, Meng;Wang, Yu;Chen, Rui;Xu, Shiyue;Sun, Xiaohong;Yang, Yan;Lin, Zeyuan;Wang, Shaogui;Huang, Heqing
肾小管间质纤维化（Renal tubulointerstitial fibrosis，TIF）是以肾小管上皮细胞向间质转化（epithelial-to-mesenchymal transition，EMT）为特征的糖尿病肾病（diabetic nephropathy，DN）的典型病理改变。龙胆苦苷（GPS）是一种具有抗炎活性的天然化合物，已被证明可以减轻肾小球硬化，而GPS是否通过调节炎症来抑制TIF尚不清楚。本研究采用糖尿病db/db小鼠模型和高糖（HG）刺激的肾小管上皮细胞（NRK-52 E），探讨GPS对TIF的影响及其机制。体内实验结果表明，GPS能有效改善糖脂代谢紊乱、肾功能不全和TIF。特别是，GPS治疗逆转了db/db小鼠肾脏中EMT标记蛋白的异常表达，包括升高的α-平滑肌肌动蛋白和波形蛋白以及降低的E-钙粘蛋白。此外，GPS还可抑制血管紧张素Ⅱ 1型受体（AT 1 R）和CK 2 α的蛋白表达及NF-κB通路的激活。重要的是，上述GPS在体内发挥的作用在体外进一步观察到在HG刺激的NRK-52 E细胞中，这是独立于其对葡萄糖和降脂活性的影响，但被AT 1 R过表达逆转。总之，我们的研究结果表明，GPS通过AT 1 R直接抑制CK 2/NF-κB炎症信号通路也可能有助于改善糖尿病TIF。
Renal tubulointerstitial fibrosis (TIF), characterized by epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, is the typical pathological alteration in diabetic nephropathy. Gentiopicroside (GPS), a natural compound with anti-inflammatory activity, has been demonstrated to alleviate glomerulosclerosis, whereas whether GPS inhibits TIF via regulating inflammation remains unclear. In this study, diabetic db/db mice and high glucose (HG)-stimulated renal tubular epithelial cells (NRK-52E) were applied to explore the effects and mechanisms of GPS on TIF. The results in vivo showed that GPS effectively improves glycolipid metabolism disorder, renal dysfunction, and TIF. In particular, GPS treatment reversed the abnormal expressions of EMT marker proteins including elevated α-smooth muscle actin and vimentin and decreased E-cadherin in the kidney of db/db mice. Moreover, GPS treatment also inhibited protein expressions of angiotensinⅡ type 1 receptor (AT1R) and CK2α and the activation of the NF-κB pathway. Importantly, the aforementioned effects of GPS acted in vivo were further observed in vitro in HG-stimulated NRK-52E cells, which were independent of its effects on glucose and lipid-lowering activity but were reversed by AT1R over-expression. Together, our results indicate that GPS that directly inhibits the CK2/NF-κB inflammatory signaling pathway via AT1R may also contribute to the amelioration of TIF in diabetes.
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